The incidence, etiology, clinical manifestations, and management of malignant hyperthermia (MH) are reviewed in Felice-Johnson, J., T. Sudds & G. Bennett, "Malignant Hyperthermia: Current Perspectives", American Journal of Hospital Pharmacy, Vol. 38, No. 5 (May, 1981), pp. 646-651. The syndrome of MH is recognized as one of the causes of anesthesia-related deaths. It is considered pharmacogenetic because both an abnormal gene and precipitating environmental factors are necessary to produce an acute MH reaction. Metabolic defects, involving a derangement of calcium dynamics, appear to be the common characteristic of susceptible individuals. Calcium release and uptake from the sarcoplasmic reticulum is altered when an individual with MH is exposed to certain anesthetic agents or triggering physical and emotional stresses. Muscle rigidity, tachycardia, tachypnea, and high fever can lead to other complications and death.
Management of an acute reaction of MH includes cooling methods to lower body temperature, hyperventilation, sodium bicarbonate control of acidosis, maintenance of fluid and electrolyte balance, and administration of dantrolene sodium. The early administration of dantrolene sodium in acute reaction of MH has been shown to rapidly alleviate the symptoms and ensuing severe complications.
Dantrolene sodium, 1-[[[5-(4-nitrophenyl)-2-furanyl]methylene]amino]-2,4-imidazolidinedione sodium salt, is commercially available as a muscle relaxant drug and is also indicated for the treatment of malignant hyperthermia; see Physicians Desk Reference, 41st Edition (1987), E. R. Barnhardt (Pub.), Medical Economics Company, Inc., page 1412. The use of dantrolene sodium as a cardiac antiarrhythmic agent is disclosed in U.S. Pat. No. 4,543,359 issued to Ellis & Moore on Sept. 24, 1985.
Azumolene is 1-[[[5-(4-bromophenyl)-2-oxazolyl]methylene]amino]-2,4-imidazolidinedione. Azumolene is disclosed to be useful as a muscle relaxant in U.S. Pat. No. 4,049,650 issued to White on Sept. 20, 1977, the disclosure of which is hereby incorporated by reference. Example V of U.S. Pat. No. 4,049,650 discloses a method for preparing azumolene.